PROJECT ABSTRACT/SUMMARY: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the death of motor neurons in the spinal cord and brain. ALS is a genetically complex disease; diverse mutations cause motor neuron death by disrupting various interrelated pathways. To date no therapy targeting a single factor can rescue motor neuron loss. Transforming Growth Factor Beta (TGF-?) is upstream of many of the pathways changed in disease and has been shown to be dysregulated in multiple ALS models. Upregulation of TGF-? signaling has been identified as neuroprotective in many neurodegenerative disease models; however, there is evidence that endogenous TGF-? signaling is disrupted in ALS. The goal of this research is to understand how TGF-? signaling directly affects motor neuron survival and gene expression in the SOD1G93A model of ALS. This application?s central hypothesis is that disease related disruption of TGF-? signaling in motor neurons contributes to their death. This hypothesis will be tested using viral therapies in a transgenic ALS animal model followed by gene expression profiling. Aim 1 will test how loss of a specific TGF-? receptor affects motor neuron survival in a motor pool particularly susceptible to disease. Aim 2 will examine how loss of SMAD7, a TGF-? antagonist upregulated in diseased motor neurons, affects this same pool. These studies will define the role of TGF-? signaling in diseased and healthy motor neurons and begin to unravel how this pathway antagonizes pro-inflammatory pathological processes in motor neurons that are vulnerable to this disease.